Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis 2308923

Abstract

Abstract Introduction Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron loss and eventual paralysis. While autoimmune mechanisms have long been suspected to contribute to ALS pathology, disease-associated antigen targets have remained elusive. Methods We analyzed if ALS was associated with increased autoreactive T cell responses towards TDP-43, SOD1, and C9orf72, compared to healthy controls. Peptide megapools consisting of 15 amino acid peptides overlapping by 10 residues spanning the entire sequence was synthesized for each protein. Fluorospot assays were used to measure T cell responses to the peptide pools by measuring release of interferon-γ (IFNγ), interleukins 5 (IL-5) and 10 (IL-10). Results We demonstrate that the ALS-associated protein C9orf72 is a major antigenic target in ALS. Epitope mapping revealed multiple immunogenic regions across the C9orf72 protein. While the reactivity was found broadly in ALS subjects, the responses were particularly high ALS donors who carried the C9orf72 hexanucleotide repeat expansion mutation in the non-coding regions of the gene. Importantly, IL-10-mediated responses were significantly higher in individuals with longer predicted survival, suggesting a regulatory and potentially protective influence on disease progression. Conclusion Together, these findings identify the first defined target of autoreactive T cell responses in ALS, and support the hypothesis that disease trajectory is in part shaped by the balance of inflammatory and counter-inflammatory T cell activity. Funding Source Supported by LJI & Kyowa Kirin, Inc. (KKNA- Kyowa Kirin North America), the Swedish Research Council (salary for E.J., grant references 2024-00175), the Freedom Together Foundation (to D.S.), and in part by the Intramural Research Program, NINDS, NIH (A. Topic Categories Neuroimmunology (NEUR)